T6 tumor immunity

immune response to tumors - cells

CD8+, CD4+, NK, macrophages, LAK

cross presentation

dendritic cells take exogenous antigens (tumor fragments) to be load on MHC class I

importance of cross presentation

CD8+ will recognize tumor fragments antigens on MHC class I

CD8+ - mechanism - 1st step

dendritic cells phagocytosed tumor antigen → load on MHC class I

CD8+ - mechanism - 2nd step

dendritic cells present tumor antigen + MHC class I to CD8+

CD8+ - mechanism - 3rd step

TCR on CD8+ recognize peptide-MHC I complex

CD8+ - mechanism - 4th step

activated CD8+ proliferate & differentiate to effector cells

CD8+ - mechanism - 5th step

CD8+ recognize tumor cells presenting same antigen as their own MHC I → kill

CD8+ - mechanism - costimulator

CD28 + B& & IL-2 from CD4+ → fully activate CD8+

CD8+ - pathway of killing

perforin-granzyme & Fas-FasL

CD4+ - functions

help CTLs by secreting cytokines & release IFN-gamma

IFN-gamma

activate macrophage & increase tumor MHC class I expression

tumor “missing self”

lose MHC class I to avoid CTL

NK cells - special ability

recognize tumor cells “missing self”

activating receptors

on NK cells → recognize stress ligands → kill tumor cells

NK killing enhanced by…

cytokines (IL-2, IL-12, IL-15) & ADCC

ADCC

NK cells express CD16 that bind to antibodies on antibody-coated tumor cells via Fc receptor

M1

anti-tumor → release ROS, nitric oxide, enzymes to kill tumor cells

M1 - activated by

IFN-gamma

M2

pro-tumor → promote growth and angiogenesis by secreting VEGF, TGF-beta, tissue repair signals

M2 - activated by

IL-13 & IL-4

inflammatory cytokines

IL-1, IL-12, IL-23, chemokines

anti-inflammatory cytokines

IL-10 & TGF-beta

CARs - components

antigen-binding part from B cells/antibodies & signaling part (from T cells)

CARs - extracellular part

from B cells

CARs - intracellular part

from T cells

CARs - antigen binding part

single chain variable fragment

CARs - antigen binding part - function

directly bind to protein antigen on tumor cell surface

CARs - signaling part

CD3zeta & costimulatory domains (CD28, 4-1BB)

CARs - signaling part - function

trigger cytotoxic machinery of T cells (perforin, granzymes, Fas-FasL)

CARs - methods

T cell collection → genetic engineering → expansion → infusion back

CARs - side effects

cytokine release syndrome, loss of target antigens, T cell exhaustion, on-target off-tumor effect

CARs - cytokine release syndrome

fever, low BP, organ stress → treat with anti-IL-6 receptor antibodies

CARs - loss of target antigens

tumor cells may stop expressing CD19/CD20

CARs - T cell exhaustion

transferred cells may become unresponsive or suppressed by tumor microenvironent

CARs - on-target off-tumor effect

kill normal B cells that also express CD19/CD20

autologous tumor-specific T cell transfer - method

collect tumor sample → TILs isolated → mix with IL-2 for expansion → TIL shipped back → lymphodepleting → patient receives expanded TILs

tumor-infiltrating lymphocytes (TILs)

recognize tumor antigen but too few/weak inside the patient

lymphodepleting chemotherapy

reduce existing immune cells to make space for new TILs

expanded TILs

target and kill tumor cells much more effectively

IL-2 with expanded TILs

help to survive, proliferate, remain active

immune checkpoint blockage - types

induction of anti-tumor immune response in lymph node & CTL-mediated killing of tumor cells

anti-CLA-4 antibody

block CLA-4 → CD28 can bind to B7 → T cells activated to become CD8+

anti-PD-1 / anti-PD-L1 antibodies

block PD-1 / PD-L → no inhibition → CTLs remain active

PD-L1

expressed on tumor cells

PD-1

expressed on CTLs

immune checkpoint blockage - side effects

autoimmune / inflammatory → colitis, hepatitis, thyroiditis, diabetes

PD-1/ PD-L1 + CTLA04 combination

stronger effect

immune checkpoint blockage - more effective, fewer side effects

anti-PD-1 / anti-PD-L1 antibodies

monoclonal antibodies therapy - types

cell surface tumor antigen, cell surface tumor antigen with conjugated drug, cell surface tumor signaling molecule

antibody specific for cell surface tumor antigen - mechanism

antibody binds directly to tumor antigens

antibody specific for cell surface tumor antigen - effects

complement-mediated tumor killing, Fc receptor-mediated phagocytosis, NK-mediated ADCC

antibody specific for cell surface tumor antigen with conjugated drug - mechanism

antibody guides drug to tumor cells by binding to their antigen → complex internalized into tumor cell → drug released → kill

antibody specific for cell surface tumor signaling molecule - mechanism

antibodies bind to growth factor receptor on tumor cells → block signaling

antibody specific for cell surface tumor signaling molecule - effect

stop tumor growth → tumor cannot survive & proliferate

antibody specific for cell surface tumor signaling molecule - examples

anti-HER2/NEU & anti-EGFR

anti-HER2/NEU

for breast cancer

anti-EGFR

for metastatic colorectal cancer, head & neck cancer

trastuzumab deruxtecan

anti-HER2 antibody linked to chemotherapy payload in breast cancer

cancer vaccines - types

vaccination with antigens of oncogenic virus & vaccination with tumor antigens

vaccination with antigens of oncogenic virus

uses viral antigens from viruses known to cause cancer → immune system produces protective antibodies and T-cell responses

vaccination with antigens of oncogenic virus - examples

HBV & HPV vaccines

vaccination with antigens of oncogenic virus - goal

prevent cancer by blocking the infection that can lead to malignancy

vaccination with tumor antigens

stimulates T cells to attack tumors already present

vaccination with tumor antigens - goal

treat existing cancers by inducing immune responses against abnormal proteins expressed by tumor cells

dendritic cell-based cancer vaccine - method

isolate dendritic cells → load tumor antigens → re-infuse → present tumor antigens to T cells → activation of tumor-specific T cells → kill

dendritic cell-based cancer vaccine - approved for

advanced prostate cancer

cytokine immunotherapy - IL-2

stimulate T and NK cells → production of pro-inflammatory cytokines (TNF, IFN-gamma)

cytokine immunotherapy - IFN-alpha

boost MGC class I on tumor cells & NK activity → inhibit tumor proliferation

cytokine immunotherapy - BCG

induce local macrophage-driven inflammation

tumor cells variants

immune system cannot fully eliminate

why tumor variants survive?

genetic instability / mutations

immune surviallance

immune system can recognize and remember tumors

tumor antigens stimulate…

adaptive immune response

tumor-specific antigens

found only on tumor cells → good target for therapy

tumor-associated antigens

found on both tumor cells & normal cells → less ideal as targets

neoantigens

newly formed antigens that arise from genetic mutations in tumor cells

antigens of oncogenic virus that have vaccines

HPV & HBV

HPV

carcinomas of uterine cervix, oropharynx, etc

HBV

hepatocellular carcinoma

overexpressed cellular proteins

normal self-proteins made in abnormally high amounts in cancer (unmutated tumor antigens)

oncofetal antigens

proteins expressed at high levels in cancer cells and developing fetus

oncofetal antigens - examples

CEA & AFP

unmutated but overexpressed oncogenes - examples

HER2/Neu

differentiation Ags normally present in tissue of origins - examples

prostate-specific antigen & CD20 (B cell lymphoma)

produce of oncogenic virus - examples

E6/E7 of HPV & EBNA-1 of EBV

tumor markers

substance made by cancer cells or normal cells responding to cancer

uses of tumor markers

estimate prognosis, determine cancer stage, detect recurrent cancer, monitor treatment response, select therapies

AFP - cancer

hepatocellular carcinoma, gonadal germ cell tumor

CEA - cancer

adenocarcinoma of colon, pancreas, lung, breast, ovary

PSA - cancer

prostate cancer

CA-125, HE4 - cancer

ovarian cancer

CA19-9 - cancer

pancreatic cancer

CA15-3 - cancer

breast cancer

human chorionic gonadotropin - cancer

gestational trophoblastic disease, gonadal germ cell tumor

neuron-specific enolase (NSE) - cancer

small cell lung cancer, neuroblastoma

lactate dehydrogenase - cancer

lymphoma, ewing’s sarcoma

breast cancer - screening

mammogram

colon and rectal cancer - screening

fecal immunochemical test, colonoscopy

cervical cancer - screening

HPV test, PAP test